Project Summary/Abstract Cortical growth and the resulting increased gyration separate humans from other species and are related to our capacity for high-order cognitive functions. Defects in neurodevelopmental processes that result in disrupted cortical folding are associated with a range of cognitive deficits in many developmental brain disorders. Accordingly, it has been a matter of great interest to understand mechanisms of the human cortical growth and folding, such as genetic and environmental effects. The areal growth and folding of the human cerebral cortex are regulated processes in space and time under tight genetic control, occurring with dramatic speed during fetal life. However, since gene expression associated with brain development can be modified by environmental factors during fetal life, cortical growth and folding must be influenced by not only fetal genotype but also intrauterine environment. As the placenta plays a vital role in shaping the fetal environment and affecting fetal growth through the exchange of oxygen and nutrients, we can hypothesize that placental transport function may be one of the important non-genetic factors that influence spatio-temporal dynamics of early human cortical growth and folding. The proposed project aims to explore the effect of placental transport function on the fetal cortical growth and folding to define non-genetic, potentially modifiable, prenatal environmental factors affecting early human brain development and subsequent postnatal clinical and behavioral outcomes. We propose a monochorionic twin analysis controlling for genetic and maternal factors and using innovative magnetic resonance imaging (MRI) and analysis methods to directly quantify fetal cortical development and placental transport function in vivo. Our scientific premise is that genotype and gestational age as well as maternal environmental factors are identical in monochorionic twins, but placental function may differ giving rise to differences in cortical development. Using structural MRI, not only global cortical growth (whole-brain cortical volume, surface area and gyrification index) but also regional geometric and topological features (position, area, depth, and the number of sulcal basins) and arrangement/patterning of primary sulci (graph-based sulcal pattern) will be quantified in fetal brains. In their corresponding placenta, placental function, characterized by oxygen transport from mother to fetal organs, will be directly assessed using in vivo quantitative OxyMRI (BOLD MRI with maternal hyperoxia) metric. We will compare and correlate differences in global and regional cortical growth and sulcal patterns with differences in OxyMRI metric in monochorionic concordant and discordant twin fetuses, and hypothesize their significant positive correlations. We will also determine which cortical regions and features are more influenced by the placental oxygen transport function. Our innovative MRI analysis will identify placental non-genetic prenatal influences on human brain development and provide a valuable reference for understanding developmental mechanisms of the human cerebral cortex.